Method for treating and preventing secondary hyperparathyroidism

ABSTRACT

A method for preventing loss of bone mass or bone mineral content in a human being suffering from secondary hyperparathyroidism by administering a sufficient amount of 1α--OH vitamin D 2 , 1α,24(S)--(OH) 2  vitamin D 2 , 1α--OH vitamin D 4  or lα,24(R)--(OH) 2  vitamin D 4 .

This is a continuation of application Ser. No. 08/798,958 filed Feb. 11,1997, now U.S. Pat. No 5,707,980 which is a continuation of U.S. patentapplication Ser. No. 08/415,488 filed Apr. 3, 1995, now U.S. Pat. No.5,602,116, which is a continuation-in-part of U.S. patent applicationSer. No. 08/119,895 filed Sep. 10, 1993, now U.S. Pat. No. 5,403,831,which is a continuation of U.S. patent application Ser. No. 07/812,056filed Dec. 17, 1991, abandoned, which is a continuation of U.S. patentapplication Ser. No. 07/569,412 filed Aug. 17. 1990, now U.S. Pat. No.5,104,864, which is a continuation of U.S. patent application Ser. No.07/227,371 filed Aug. 2, 1988, abandoned.

BACKGROUND OF THE INVENTION

Numerous metabolic bone disorders are known which are characterized byloss of bone mass or bone mineral. These disorders includepostmenopausal osteoporosis, senile osteoporosis, corticosteroid-inducedosteopenia, anticonvulsant osteomalacia and renal osteodystrophy. Ofthese disorders, renal osteodystrophy is encountered in end-stage renaldisease patients undergoing chronic dialysis.

As a group, these bone depletive disorders are a major and growingpublic health problem in the United States. Together, they cause morethan 1 million bone fractures per year, primarily of the spine, hip, anddistal forearm, and result in an annual cost above $10 billion to theAmerican society. Unfortunately, the incidence of these bone disorderswill rise significantly as the mean age of the U.S. population continuesto increase.

Despite differing etiologies, the aforementioned metabolic bonedisorders develop during an extended period of negative calcium balance.This commonality of the disorders suggests that agents which stimulateintestinal calcium absorption and otherwise regulate calcium homeostasismay be effective in restoring calcium balance, thereby treating orpreventing the development of such bone disorders.

It has long been known that vitamin D plays a critical role instimulating calcium absorption and regulating calcium metabolism. Thediscovery of the active forms of vitamin D in the 1970's M. F. Holick etal., Proc. Natl. Acad. Sci. USA 68, 803-804 (1971); G. Jones et al.,Biochemistry 14, 1250-1256 (1975)! and active vitamin D analogues M. F.Holick. et al., Science 180, 190, 191 (1973); H. Y. Lam et al., Science186, 1038-1040 (1974)!, caused much excitement and speculation about theusefulness of these compounds in the treatment of bone depletivedisorders.

Animal and early clinical studies examining the effects of these activevitamin D compounds suggested that such agents would be useful inrestoring calcium balance. However, the best indicator of the efficacyof vitamin D compounds to prevent or treat depletive bone disorders isbone itself (or, in the case of renal osteodystrophy, serum levels ofparathyroid hormone (PTH)) rather than calcium absorption or calciumbalance. Certain clinical studies with 1α,25--(OH)₂ vitamin D₃, and1α--OH vitamin D₃ indicate that the ability of these agents to restorelost bone mass or bone mineral content is dose related. See, S. M. Ott,C. H. Chesnut, Annals of Int. Med. 1989; 110:267-274; J. C. Gallagher etal., Annals of Int. Med. 1990; 113:649-655; J. Aloia et al., Amer. J.Med. 84:401-08 (1988)! M. Shiraki et al., Endocrinol. Japan 32, 305-315(1985)!.

These studies also indicate that at the dosage ranges required for theseagents to be truly effective, toxicity in the form of hypercalcemia andhypercalciuria becomes a major problem. Attempts to increase the amountof 1α,25--(OH)₂ vitamin D₃ above 0.5 μg/day have frequently resulted intoxicity. At dosage levels below 0.5 μg/day, clinically significanteffects are rarely observed on bone. See G. F. Jensen et al., Clin.Endocrinol. 16, 515-524 (1982); C. Christiansen et al., Eur. J. Clin.Invest. 11, 305-309 (1981)!. Doses of 2 μg/day of 1α--OH vitamin D₃ werefound to have efficacy in increasing bone mass in patients exhibitingsenile osteoporosis O. H. Sorensen et al., Clin. Endocrinol. 7,169S-175S (1977)!. Data from clinical studies in Japan, a populationthat has low calcium intake, indicate that efficacy is found with 1α--OHvitamin D₃ when administered at 1 μg/day M. Shiraki et al., Endocrinol.Japan. 32:305-315 (1985); H. Orimo et al., Bone and Mineral 3, 47-52(1987)!. However, at 2 μg/day, toxicity with 1α--OH vitamin D₃ occurs inapproximately 67 percent of the patients, and at 1 μg/day thispercentage is approximately 20 percent.

Thus, the prior art teaches that due to their toxicity, 1-hydroxylatedvitamin D compounds can only be administered at dosages that are, atbest, modestly beneficial in preventing or treating loss of bone or bonemineral content. Indeed, Aloia recommends that alternative routes ofadministration be sought which might avoid the toxicity problems andallow higher dosage levels to be achieved. J. Aloia et al., Amer. J.Med. 84:401408 (1988)!.

Despite reported toxicities of 1α--OH vitamin D₃ and 1α,25--(OH)₂vitamin D₃, these two compounds remain the drugs of choice for many bonedepletive disease treatments. For example, in end stage renal disease,these two drugs remain the only approved forms of 1α-hydroxylatedvitamin D for treating or preventing secondary hyperparathyroidism,although both drugs are not currently approved in all majorpharmaceutical markets.

At present, in the United States, end stage renal disease afflictsapproximately 200,000 individuals. In this disease, there is aprogressive loss of cells of the proximal nephrons, the primary site forthe synthesis of the vitamin D hormones (collectively "1α,25--(OH)₂ D")from 25-hydroxyvitamin D₃ and 25-hydroxyvitamin D₂. In addition, theloss of functioning nephrons leads to retention of excess phosphoruswhich reduces the activity of the renal 25-hydroxyvitaminD-1α-hydroxylase, the enzyme which catalyzes the reaction to produce theD hormones. These two events account for the low serum levels of1α,25--(OH)₂ D commonly found in patients with mild to moderate endstage renal disease.

Reduced serum levels of 1α,25--(OH)₂ D cause increased, and ultimatelyexcessive, secretion of PTH by direct and indirect mechanisms. Theresulting hyperparathyroidism leads to markedly increased bone turnoverand its sequela of renal osteodystrophy, which may include a variety ofother diseases, such as, osteitis fibrosa cystica, osteomalacia,osteoporosis, extraskeletal calcification and related disorders, e.g.,bone pain, periarticular inflammation and Mockerberg's sclerosis.Reduced serum levels of 1α,25--(OH)₂ D also can cause muscle weaknessand growth retardation with skeletal deformities (most often seen inpediatric patients).

All previous clinical studies of hormonally active vitamin D drugs inend stage renal disease patients have focused exclusively on compoundsderived from vitamin D₃. Use of 1α,25--(OH)₂ D₃ and 1α--OH-vitamin D₃ asreplacement therapy seeks to treat or prevent renal osteodystrophy bytreating or preventing secondary hyperparathyroidism in end stage renaldisease patients. As noted above, 1α,25--(OH)₂ D₃ often causes toxicside effects (hypercalcemia and hyperphosphatemia) at dosages above 0.5μg, especially when concomitantly administered calcium phosphate bindersare used to control serum phosphorus. The minimum effective dose forpreventing secondary hyperparathyroidism is in the range of 0.25 to 0.50μg/day; most patients respond to oral treatment doses of 0.5 to 1.0μg/day or intravenous doses between 0.5 and 3.0 μg three times per week.As described above, the other commonly used vitamin D drug is 1α--OH--D₃which often causes toxic effects at dosages over 1.0 μg/day, especiallywhen used with calcium phosphate binders. The minimum effective dosagefor preventing secondary hyperparathyroidism is in the range of 0.25 to1.0 μg/day, and most patients require treatment dosages of 1.0 μg/day ormore. When either drug, 1α,25--(OH)₂ D₃ or 1α--OH--D₃, is administeredin higher dosages, both efficacy and toxicity are found to increase.Thus, the hormonally active vitamin D₃ compounds are limited in theirtherapeutic usefulness due to their inherent toxicities.

To reduce the incidence of toxic side effects with 1α,25--(OH)₂ D₃ or1α--OH--D₃, a low calcium dialysate with an ionized calciumconcentration of 1.25 mM has been developed. However, it has been foundthat use of the low calcium dialysate has lead to higher serum PTH andphosphorus levels in patients who do not receive increased doses of oralcalcium supplements and phosphate binders. When the dosages of calciumsupplements and phosphate binders are increased, serum levels ofphosphorus become controlled, but the incidence of hypercalcemia risesmarkedly. Thus, there are many problems associated with the use ofcurrent vitamin D therapies for secondary hyperparathyroidism.

Notwithstanding these known problems with use of the hormonally activevitamin D₃ for secondary hyperparathyroidism, the art has not adequatelyresponded to date with the introduction of other vitamin compounds,derivatives or analogs that possess less inherent toxicity.

SUMMARY OF THE INVENTION

The present invention provides a method for treating or preventinghyperparathyroidism secondary to end stage renal disease by lowering (ormaintaining low) serum parathyroid hormone levels in a patient sufferingfrom the disease. The method at the same time ameliorates or preventsthe renal osteodystrophy which can develop in such patients.

The foregoing, and other advantages of the present invention, arerealized in one aspect thereof in a method for lowering serum (orplasma) PTH in patients suffering from hyperparathyroidism secondary toend stage renal disease, comprising: administering to these patients aneffective amount of a vitamin D analog of formula (I), as describedhereinbelow, to lower the serum PTH level. The analog of formula (I) isany active vitamin D compound which has potent biological activity butlow calcemic activity relative to the active forms of vitamin D₃.Preferably such compounds are 1α--OH-vitamin D₂ ; 1α,24(S)--(OH)₂-vitamin D₂ ; 1α--OH-vitamin D₄ ; or 1α,24(R)--(OH)₂ -vitamin D₄. Theanalog of formula (I) is administered in a dosage amount of 1 to about100 μg/week. As used herein, the term "vitamin D analog" is meant torefer to compounds having vitamin D hormonal bioactivity. It is alsonoted that a shorthand notation is often used for the D hormones, e.g.,1α-hydroxy vitamin D₂ may be referred to as 1α--OH-vitamin D₂ or simply1α--OH--D₂.

In another aspect, the invention is a pharmaceutical composition havingserum (or plasma) PTH lowering activity, which includes, in unit dosageform, an effective amount of a vitamin D analog which is 1α--OH-vitaminD₂ 1α,24(S)--(OH)₂ -vitamin D₂ ; 1α--OH-vitamin D₄ ; or 1α,24(R)--(OH)₂-vitamin D₄ ; and a pharmaceutically acceptable excipient.

The invention also relates to a method for achieving an effect in apatient comprising administering an effective amount of the compositionof present invention to the patient wherein the effect is lowering ormaintaining lowered serum parathyroid hormone levels, and thusdecreasing loss of bone mass or bone mineral content.

The invention further relates to, as an article of manufacture, a tablethaving activity to lower parathyroid hormone level as measured by bloodserum level of parathyroid hormone over time after ingestion,comprising: from about 0.25 to 5.0 μg of a vitamin D analog selectedfrom the group consisting of 1α--OH-vitamin D₂ ; 1α,24(S)--(OH)₂-vitamin D₂ ; 1α--OH-vitamin D₄ ; and 1α,24(R)--(OH)₂ -vitamin D₄.

The treatment method of the present invention is an alternative toconventional therapy with 1α,25--(OH)₂ vitamin D₃ or 1α--OH-vitamin D₃ ;the method is characterized by providing an active vitamin D compoundhaving equivalent bioactivity but much lower toxicity than theseconventional therapies. This is true especially in the case where oralcalcium phosphate binders are used concomitantly to control serumphosphorus. As such, the method addresses a long felt need in secondaryhyperparathyroidism therapy.

A comparison of 1α--OH-vitamin D₂ to 1α--OH-vitamin D₃ has beenconducted. 1α--OH-vitamin D₂ is equally active as 1α--OH-vitamin D₃ inthe healing of rickets, in the stimulation of intestinal calciumabsorption and in the elevation of serum inorganic phosphorous ofrachitic rats. G. Sjoden et al., J. Nutr. 114, 2043-2946 (1984)!. In thesame laboratory animal, the inventors also have found that1α--OH-vitamin D₂ is 5 to 15 times less toxic than 1α--OH-vitamin D₃see, also, G. Sjoden et al., Proc. Soc. Exp. Biol. Med. 178, 432-436(1985)!. It has now been found that, for example, 1α--OH-vitamin D₂ maybe safely administered for up to two years to human subjectsexperiencing or having a tendency toward loss of bone mass or bonemineral content at dosages greater than 3 μg/day.

The present invention is also intended to be used in all bone depletivedisorders which respond to administration of active forms of vitamin D.

Other advantages and a fuller appreciation of specific adaptations,compositional variations, and physical attributes will be gained upon anexamination of the following detailed description of preferredembodiments.

DETAILED DESCRIPTION

The present invention relates broadly to bone depletive disorders.However, the method of the present invention is most particularlyadapted for use in ameliorating or preventing hyperparathyroidismsecondary to end stage renal disease. The method also ameliorates orprevents the concomitant renal osteodystrophy of these patients withthis disease. Accordingly, the present invention will now be describedin detail with respect to such endeavors; however, those skilled in theart will appreciate that such a description of the invention is meant tobe exemplary only and should not be viewed as limitative on the fullscope thereof.

More specifically, the present invention relates to therapeutic methodsfor lowering the excessively high blood levels of parathyroid hormone(PTH) which are secondary to end stage renal disease. The method inaccordance with the present invention has significantly less resultanthypercalcemia and hyperphosphatemia, especially in patients who use oralcalcium phosphate binders to control serum phosphorus levels. Theseattributes are achieved through a novel treatment of a patient sufferingfrom secondary hyperparathyroidism with a vitamin D analog of formula(I) as described hereinbelow.

In accordance with the invention, it has been found that when theanalogs of formula (I) are administered to end stage renal diseasepatients with elevated serum parathyroid hormone, PTH concentration islowered with significantly less hypercalcemia and hyperphosphatemia thanis observed after the same amount of activated vitamin D administered inpreviously known formulations. Thus, the compounds of formula (I) havean improved therapeutic index relative to vitamin D₃ analogs.

The vitamin D analogs in accordance with the present invention have thegeneral formula: ##STR1## where A¹ and A² are each either H or togetherform a carbon-carbon double bond, and where R¹ either a hydrogen orhydroxyl. The analogs of formula (I) are substantially less toxic thantheir vitamin D₃ counterparts when administered to patients experiencinghyperparathyroidism secondary to end stage renal disease. For patientsusing oral calcium phosphate binders, administration of the analogs offormula (I) at dosage levels higher than possible with the vitamin D₃compounds provides greater efficacy than heretofore possible in treatingsecondary hyperparathyroidism.

Preferred among the analogs of formula (I) are: 1α-hydroxyvitamin D₂(also known as 1α-hydroxyergocalciferol); 1α-hydroxyvitamin D₄ ;1α,24(S)-dihydroxyvitamin D₂ and 1α,24(R)-dihydroxyvitamin D₄. Mostpreferred is 1α-hydroxyvitamin D₂, a prodrug for 1α,25-dihydroxyvitaminD₂ which is an endogenous metabolite of vitamin D₂.

It is noted that the medical community currently views vitamin D₃compounds as biologically indistinguishable from the correspondingvitamin D₂ compounds. This is evident from the indiscriminate inclusionof either vitamin D₂ or D₃ in vitamin supplements prepared for humanuse, and from the interchangeable use of either vitamin in treating bonediseases caused by vitamin D deficiency. Curiously, medical expertsconsider the hormonally active forms of the two vitamins to beequivalent despite lack of confirmation from a single human study. (Itis also interestingly noted that vitamin D₄ is described in The MerckIndex (Merck Index, 11th ed. (1989) p. 9932) as having doubtfulbiological activity.)

In parent application, Ser. No. 08/119,895 and its parent application,now U.S. Pat. No. 5,104,864, it has been shown that 1α--OH-vitamin D₂has the same biopotency as 1α--OH-vitamin D₃ and 1α,25--(OH)₂ -vitaminD₃ but is much less toxic. Even dosages up to 10 μg/day of1α--OH-vitamin D₂ in women with postmenopausal osteoporosis (in bothopen label and double blind testing) exhibited only mild hypercalciuria(>300 mg/24 hrs), and marked hypercalcemia (>11.0 mg/dL) solely due to1α--OH-vitamin D₂ was not evident. Additionally, the compound did notadversely affect kidney function, as determined by creatinine clearanceand BUN; nor did it increase urinary excretion of hydroxyproline,indicating the absence of any stimulatory effect on bone resorption.Administration of 1α--OH-vitamin D₂ to healthy adult males in dosages upto 8 μg/day showed no hypercalcemia or other adverse effects.

The analogs of formula (I) are useful as active compounds inpharmaceutical compositions. The pharmacologically active analogs ofthis invention can be processed in accordance with conventional methodsof pharmacy to produce pharmaceutical agents for administration topatients, e.g., in admixtures with conventional excipients such aspharmaceutically acceptable organic or inorganic carrier substancessuitable for parenteral, enteral (e.g., oral) or topical applicationwhich do not deleteriously react with the active compounds. Suitablepharmaceutically acceptable carriers include but are not limited towater, salt (buffer) solutions, alcohols, gum arabic, mineral andvegetable oils, benzyl alcohols, polyethylene glycols, gelatine,carbohydrates such as lactose, amylose or starch, magnesium stearate,talc, silicic acid, viscous paraffin, perfume oil, fatty acidmonoglycerides and diglycerides, pentaerythritol fatty acid esters,hydroxy methylcellulose, polyvinyl pyrrolidone, etc. The pharmaceuticalpreparations can be sterilized and if desired mixed with auxiliaryagents, e.g., lubricants, preservatives, stabilizers, wetting agents,emulsifiers, salts for influencing osmotic pressure, buffers, coloring,flavoring and/or aromatic active compounds. If a solid carrier is used,the dosage form of the analogs may be tablets, capsules, powders,suppositories, or lozenges. If a liquid carrier is used, soft gelatincapsules, transdermal patches, aerosol sprays, topical creams, syrups orliquid suspensions, emulsions or solutions may be the dosage form.

For parenteral application, particularly suitable are injectable,sterile solutions, preferably oily or aqueous solutions, as well assuspensions, emulsions, or implants, including suppositories. Ampoulesare convenient unit dosages. The dosage of the analogs in accordancewith the present invention for parenteral administration generally isabout 1-30 μg given 1 to 3 times per week.

For enteral application, particularly suitable are tablets, dragees,liquids, drops, suppositories, or capsules. A syrup, elixir, or the likecan be used wherein a sweetened vehicle is employed.

Sustained or directed release compositions can be formulated, e.g.,liposomes or those wherein the active compound is protected withdifferentially degradable coatings, e.g., by microencapsulation,multiple coatings, etc. It is also possible to freeze-dry the newcompounds and use the lypolizates obtained, for example, for thepreparation of products for injection.

For topical application, there are employed as nonsprayable forms,viscous to semi-solid or solid forms comprising a carrier compatiblewith topical application and having a dynamic viscosity preferablygreater than water. Suitable formulations include but are not limited tosolutions, suspensions, emulsions, creams, ointments, powders,liniments, salves, aerosols, etc., which are, if desired, sterilized ormixed with auxiliary agents, e.g., preservatives, etc.

Oral administration is preferred. Generally, the analogs of thisinvention are dispensed by unit dosage form comprising about 0.25 toabout 5.0 μg in a pharmaceutically acceptable carrier per unit dosage.The dosage of the analogs according to this invention generally is about1 to about 100 μg/week, preferably about 3 to about 25 μg/week.

It will be appreciated that the actual preferred amounts of activeanalog in a specific case will vary according to the specific compoundbeing utilized, the particular compositions formulated, the mode ofapplication, and the particular situs being treated. Dosages can bedetermined using conventional considerations, e.g., by customarycomparison of the differential activities of the subject compounds andof a known agent, e.g. by means of an appropriate conventionalpharmacological protocol.

The specific doses for each particular patient depend on a wide varietyof factors, for example, on the efficacy of the specific compoundemployed, on the age, body weight, general state of health, sex, on thediet, on the timing and mode of administration, on the rate ofexcretion, and on medicaments used in combination and the severity ofthe particular disorder to which the therapy is applied.

It is possible, if desired, to produce the metabolites of certain onesof the analogs of formula (I), in particular by nonchemical means. Forthis purpose, it is possible to convert them into a suitable form foradministration together with at least one vehicle or auxiliary and,where appropriate, combined with one or more other active compounds.

The dosage forms may also contain adjuvants, such as preserving orstabilizing adjuvants. They may also contain other therapeuticallyvaluable substances or may contain more than one of the compoundsspecified herein and in the claims in admixture.

Bulk quantities of the vitamin D analogs for the practice of thisinvention can be readily obtained in accordance with the processes ofU.S. Pat. Nos. 3,907,843; 4,195,027; 4,202,829; 4,234,495; 4,260,549;4,555,364; and 4,554,106 and U.S. patent application Ser. Nos.08/275,641 and 08/296,084.

As described hereinbefore, the analogs of formula (I) are preferablyadministered to the human patients in oral dosage formulation. As ananalog in accordance with the present invention is released from theoral dosage formulation, it is absorbed from the intestine into theblood.

The present invention is further explained by the following exampleswhich should not be construed by way of limiting the scope of thepresent invention.

EXAMPLE 1 Study Demonstrating Better Safety

The low toxicity of 1α--OH-vitamin D₂ in human patients was demonstratedin a clinical study involving 15 postmenopausal osteoporotic women. J.Bone Min. Res.; 1994; 9:607-614.! The selected patients were between 55and 75 years of age, and exhibited L2-L3 vertebral bone mineral density("BMD") between 0.7 and 1.05 g/cm², as determined by measurements with aLUNAR dual-photon absorptiometer. (The mean bone mineral density inwomen with osteoporosis is about 0.85±0.17 g/cm², so that these limitscorrespond to about the 15th to 85th percentiles.)

On admission to the study, all patients received instruction onselecting a daily diet containing 400 to 600 mg of calcium. Complianceto this diet was verified at weekly intervals by 24-hour food recordsand by interviews with each patient.

All patients completed a one-week baseline period, a five- to seven-weektreatment period, and a one-week post-treatment observation period.During the treatment period, patients orally self-administered1α--OH-vitamin D₂ at an initial dose of 0.5 μg/day for the first week,and at successively higher doses of 1.0, 2.0, 4.0, 5.0, 8.0 and 10.0μg/day in each of the following weeks. All doses were administeredbefore breakfast.

Blood and urine chemistries were monitored on a weekly basis throughoutthe study. Key blood chemistries included fasting serum levels ofcalcium, phosphorus, osteocalcin, creatinine and blood urea nitrogen.Key urine chemistries included 24-hour excretion of calcium, phosphorusand creatinine.

Data from the study clearly demonstrated that 1α--OH-vitamin D₂ can besafely administered for short periods at high dose levels. Inparticular, the compound did not adversely affect kidney function, asdetermined by creatinine clearance and blood levels of urea nitrogen;nor did it increase urinary excretion of hydroxyproline, indicating theabsence of any stimulatory effect on bone resorption. The compound hadno effect on any routinely monitored serum chemistries, indicating theabsence of adverse metabolic effects.

A positive effect of 1α--OH-vitamin D₂ on calcium homeostasis wasevident from dose-related increases observed in 24-hour urinary calciumlevels, confirming that the compound increases intestinal calciumabsorption, and from dose-related increases in serum osteocalcin,suggesting that the compound directly stimulates bone formation.

EXAMPLE 2 Study Demonstrating Safety and Efficacy for Human Osteoporosis

The safety and efficacy of 1α--OH-vitamin D₂ as an oral treatment forosteoporosis was confirmed in a study involving 60 postmenopausalosteoporotic outpatients. The selected subjects had ages between 60 and70 years, and exhibited L2-L3 vertebral BMD between 0.7 and 1.05 g/cm²,as determined by dual-energy x-ray absorptiometry (DEXA). Exclusioncriteria encompassed significant medical disorders and recent use ofmedications known to affect bone or calcium metabolism.

On admission to the study, each subject was assigned at random to one oftwo treatment groups; one group received up to a 104-week course oftherapy with 1α--OH-vitamin D₂ ; the other received only placebotherapy. All subjects received instruction on selecting a daily dietcontaining 700-900 mg of calcium and were advised to adhere to this dietover the course of the study. Compliance to the diet was verified atregular intervals by 24-hour food records and by interviews with eachsubject.

During the treatment period, subjects from one group orallyself-administered 1α--OH-vitamin D₂ at an initial dosage of 1.0 μg/dayfor one week, and increased the dosage to 2.0, 3.0, 4.0 μg/day in eachof the following weeks, to a maximum dosage of 5.0 μg/day. The dosagefor any given subject was increased in this way until the rate ofurinary calcium excretion was elevated to approximately 275-300 mg/24hours, at which point the subject held the dosage constant at thehighest level attained. Subjects from the second group self-administereda matching placebo medication every day, titrating the apparent dosageupwards in the same manner as subjects being treated with 1α--OH-vitaminD₂.

Spinal and femoral neck BMD were measured in all subjects by DEXA at thebeginning of the study, and at six-month intervals thereafter.Intestinal calcium absorption was estimated in all subjects by a singleisotope technique at the beginning of the study, and at 12-monthintervals. Serum levels of vitamin D metabolites were determined byradioreceptor binding assays at baseline and at six-month intervals.Serum osteocalcin, serum PTH and urine hydroxyproline also weredetermined at baseline and at six-month intervals.

Other blood and urine chemistries were monitored at regular intervalsduring the treatment period. These chemistries included serum calcium,serum ionized calcium, urine calcium, blood urea nitrogen, serumcreatinine and creatinine clearance. Kidney-ureter-bladder (SUB) x-rayswere obtained at baseline and at 12-month intervals thereafter.

The results of the study are summarized below:

Subjects: Sixty subjects enrolled in what was originally intended to bea 52-week study. Of these 60 subjects, 55 completed one year oftreatment (28 active; 27 placebo); and 41 subjects completed an optionalsecond year of treatment.

Test Drug Dosages: The average prescribed dosage for subjects whoreceived 1α--OH-vitamin D₂ was 4.2 μg/day at 52 weeks and 3.6 μg/day at104 weeks. The average prescribed dosage for placebo subjects was anapparent 4.8 μg/day at 52 weeks and 4.8 μg/day at 104 weeks.

Exclusions: One subject failed to comply with the prescribed dosage oftest drug, as confirmed by an absence of serum 1α,25-dihydroxyvitamin D₂at any time during the study. Data for this subject were excluded fromanalysis. Three patients were diagnosed with hyperparathyroidism whenthe PTH assays were completed (in batch) at the study's conclusion; datafor these subjects were excluded from analysis. No subjects wereexcluded from analysis for noncompliance with the required dietarycalcium intake of 700-900 mg/day.

Episodes of Hypercalcemia/Hypercalciuria: Marked hypercalcemia (>10.8mg/dL) occurred in one subject in association with an intercurrentillnes. The prescribed dosage of 1α--OH-vitamin D₂ at the time of thisepisode was 5.0 μg/day. Moderate hypercalcemia (10.4-10.8 mg/dL)occurred in two subjects over the course of the study at prescribeddosages of 5.0 μg/day. Mild hypercalcemia (10.2-10.4 mg/dL) occurred infour subjects in the first year, and in two subjects in the second year.Hypercalciuria was observed occasionally over the two-year study in 17subjects treated with 1α--OH-vitamin D₂.

Serum Calcium/Ionized Calcium: Mean serum calcium was approximately 0.1to 0.2 mg/dL higher in subjects treated with 1α--OH-vitamin D₂ than insubjects treated with placebo. This difference was significant (P<0.05)only during the second year of treatment. Mean serum ionized calcium wasapproximately 0.05 to 0.10 mg/dL higher in subjects treated with1α--OH-vitamin D₂.

Urine Calcium: Mean urine calcium increased during the initial titrationperiod in a dose-response fashion. After titration, mean urine calciumwas 50 to 130% higher (P<001) with 1α--OH-vitamin D₂ treatment than withplacebo treatment.

Kidney Function: No significant changes were observed with long-term1α--OH-vitamin D₂ treatment in BUN, serum creatinine or creatinineclearance. KUB x-rays revealed no abnormalities in either treatmentgroup throughout the course of the study.

Bone: Bone mineral density (BMD) in the L2-L4 vertebrae progressivelyincreased with 1α--OH-vitamin D₂ treatment and decreased with placebotreatment over the two-year study. The difference in spinal BMD betweenthe treatment groups became statistically significant (P<0.05) after 24months of treatment. Similar changes were observed in femoral neck BMDwith statistically significant differences observed after 18 months(P<0.001) and 24 months (P<0.05) of treatment.

Calcium Uptake: Intestinal absorption of orally administered ⁴⁵ Caincreased by 40% (P<0.001) after 52 weeks of 1α--OH-vitamin D₂ therapy,and by 29% (P<0.5) after 104 weeks of 1α--OH-vitamin D₂ therapy,relative to placebo control.

Vitamin D Metabolites: Treatment with 1α--OH-vitamin D₂ causedprogressive increases in mean serum total 1α,25-dyhydroxyvitamin D from21% (P<0.05) at six months to 49% (P<0.01) at 24 months relative toplacebo therapy. This increase resulted from a dramatic rise in serum1α,25-dihydroxyvitamin D₂ which was partially offset by a 50+% decreasein serum 1α,25-dihydroxyvitamin D₃. No treatment related changes wereapparent in serum total 25-hydroxyvitamin D.

Biochemical Parameters:

Serum levels of PTH decreased with 1α--OH-vitamin D₂ therapy by 17% at52 weeks and by 25% at 1-4 weeks, relative to placebo therapy.

Serum levels of osteocalcin were unchanged with long-term 1α--OH-vitaminD₂ therapy.

Fasting urine hydroxyproline:creatinine ratio tended to decrease withlong-term 1α--OH-vitamin D₂ treatment but the observed differencesbetween the 1α--OH-vitamin D₂ and placebo treatment groups were notsignificantly different.

The results of this study clearly indicated that 1α--OH-vitamin D₂ canbe tolerated in higher long-term dosages than the commonly used vitaminD₃ analogues. They also showed that 1α--OH-vitamin D₂ is well toleratedin postmenopausal women at long-term dosages in the range of 2.0 to 3.0μg/day, provided that individuals exhibiting abnormally high urinecalcium levels (when not receiving vitamin D therapy) are excluded fromtreatment. Long-term administration of such high dosages of1α--OH-vitamin D₂ significantly reduced bone loss at the spine andfemoral neck, the most frequent sites of osteoporotic fractures. Thesepositive effects on bone were accompanied by a sustained increase inintestinal calcium absorption and a sustained decrease in serum PTH.They were not accompanied by clear long-term trends in serum osteocalcinand urine hydroxyproline. Taken together, the results of this studydemonstrate that 1α--OH-vitamin D₂ is safe and effective in thetreatment of postmenopausal or senile osteoporosis.

EXAMPLE 3 Open Label Study in End Stage Renal Disease PatientsExhibiting Secondary Hyperparathyroidism

Five end stage renal disease patients were enrolled in an open labelstudy. The selected patients had ages between 36 and 72 years and hadbeen on hemodialysis for at least 4 months prior to enrollment. Thepatients each had an average serum phosphorus in the range of 3.0 toless than or equal to 6.9 mg/dL during the two months prior toenrollment (often controlled by oral calcium phosphate binders), and hada history of elevated serum PTH values of greater than 400 pg/mL whennot receiving 1α,25--(OH)₂ -vitamin D₃ therapy.

Each patient had been receiving 1α,25--(OH)₂ vitamin D₃ prior toenrollment, and discontinued the 1α,25--(OH)₂ vitamin D₃ therapy foreight weeks prior to receiving 1α--OH-vitamin D₂. After 8 weeks, thepatients received treatment of 1α--OH-vitamin D₂ at a dosage of 4 μg/dayfor 6 weeks. Throughout the eight-week washout period and the treatmentperiod, patients were monitored weekly or biweekly for serum intact PTHlevel and weekly for excessive elevation in serum levels of calcium andphosphorus.

Throughout the washout period and treatment period, patients underwentroutine hemodialysis (3 times per week) using a 1.25 mM calciumdialysate. They also ingested significant amounts of calcium phosphatebinders (1-10 g elemental Ca) to keep serum phosphorus levels below 6.9mg/dL.

Baseline serum PTH was 480±21; SCa (mg/dl), 9.8±0.3 and serum phosphorus(mg/dl), 5.1±0.2. In three patients, serum PTH decreased by 68%, 74% and87% after two weeks. In the other two patients, serum PTH declined by33% in one and 3% in the other after four weeks. Overall, serum PTHdecreased by 49±17% and 33±9% after two and four weeks of 1α--OH-vitaminD₂, respectively, (p<0.05). Serum calcium was 10.2±0.4 (p<0.05) and9.8±0.2 (NS) and serum phosphorus was 5.4±0.5 and 5.5±0.8 at two andfour weeks, respectively (NS). A rise in serum PTH from the second tofourth weeks of 1α--OH-vitamin D₂ occurred when 1α--OH-vitamin D₂ waswithheld in three patients with serum PTH<130; they developed mildhypercalcemia (serum calcium, 10.3-11.4) that reversed after stopping1α--OH-vitamin D₂. No other adverse effects occurred. At 4-6 weeks of1α--OH-vitamin D₂ treatment of 4 μg, thrice weekly, four of fivepatients were in the target range of serum PTH; serum calcium was10.0±0.2 and serum phosphorus, 5.3±0.2 mg/dl. The patient who failed torespond to six weeks of 1α--OH-vitamin D₂ treatment had a delayedresponse to both intravenous and oral calcitriol earlier, requiringseveral months of treatment before serum PTH fell. Serum PTH values inthis patient fell by 38% after eight weeks of 1α--OH-vitamin D₂treatment. These dates show that 1α--OH-vitamin D₂ is efficacious andsafe for the control of secondary hyperparathyroidism in end stage renaldisease patients.

EXAMPLE 4 Double Blind Study of Bone in End Stage Renal Disease Patients

A twelve-month double-blind placebo-controlled clinical trial isconducted with thirty-five men and women with renal disease who areundergoing chronic hemodialysis. All patients enter an eight-weekcontrol period during which time they receive a maintenance dose ofvitamin D₃ (400 IU/day). After this control period, the patients arerandomized into two treatment groups: one group receives a constantdosage of 1α--OH-vitamin D₂ (u.i.d.; a dosage greater than 3.0 μg/day)and the other group receives a matching placebo. Both treatment groupsreceive a maintenance dosage of vitamin D₃, maintain a normal intake ofdietary calcium, and refrain from using calcium supplements. Oralcalcium phosphate binders are used as necessary to maintain serum levelsof phosphorus below 7.0 mg/dL. Efficacy is evaluated by pre- andpost-treatment comparisons of the two patient groups with regard to (a)direct measurements of intestinal calcium absorption, (b) total bodycalcium retention, (c) radial and spinal bone mineral density, and (d)determinations of serum calcium and osteocalcin. Safety is evaluated byregular monitoring of serum calcium.

Analysis of the clinical data show that 1α--OH-vitamin D₂ significantlyincreases serum osteocalcin levels and intestinal calcium absorption, asdetermined by direct measurement using a double-isotope technique.Patients treated with this compound show normalized serum calciumlevels, stable values for total body calcium, and stable radial andspinal bone densities relative to baseline values. In contrast, patientstreated with placebo show frequent hypocalcemia, significant reductionsin total body calcium and radial and spinal bone density. Aninsignificant incidence of hypercalcemia is observed in the treatedgroup.

EXAMPLE 5 Double-Blind Study in End Stage Renal Disease (ESRD) PatientsExhibiting Secondary Hyperparathyroidism

Up to 120 ESRD (End Stage Renal Disease) patients undergoing chronichemodialysis are studied in a multicenter, double-blind,placebo-controlled study based in two major U.S. metropolitan areas. Theselected patients reside in two major metropolitan areas within thecontinental U.S., have ages between 20 and 75 years and have a historyof secondary hyperparathyroidism. They have been on hemodialysis for atleast four months, have a normal (or near normal) serum albumin, andhave controlled serum phosphorus (often by using oral calcium phosphatebinders).

On admission to the study, each patient is assigned at random to one oftwo treatment groups. One of these groups receives two consecutive12-week courses of therapy with 1α--OH-vitamin D₂ ; the other receives a12-week course of therapy with 1α--OH-vitamin D₂ followed, withoutinterruption, by a 12-week course of placebo therapy. Each patientdiscontinues any 1α,25--OH₂ -vitamin D₃ therapy for eight weeks prior toinitiating 1α--OH-vitamin D₂ therapy (4 μg/day). Throughout thiseight-week washout (or control) period and the two subsequent 12-weektreatment periods, patients are monitored weekly for serum calcium andphosphorus. Serum intact PTH is monitored weekly or biweekly, andbone-specific serum markers, serum vitamin D metabolites, serum albumin,blood chemistries, hemoglobin and hematocrit are monitored at selectedintervals.

During the study, patients undergo routine hemodialysis (three times perweek) using a 1.24 mM calcium dialysate and ingest calcium phosphatebinders (such as calcium carbonate or calcium acetate) in an amountsufficient to keep serum phosphate controlled (≦6.9 mg/dL). Patients whodevelop persistent mild hypercalcemia or mild hyperphosphatemia duringthe treatment periods reduce their 1α--OH-vitamin D₂ dosage to 4 μgthree times per week (or lower). Patients who develop markedhypercalcemia or marked hyperphosphatemia immediately suspend treatment.Such patients are monitored at twice weekly intervals until the serumcalcium or phosphorus is normalized, and resume 1α--OH-vitamin D₂ dosingat a rate which is 4 μg three times per week (or lower).

During the eight-week washout period, the mean serum level of PTHincreases progressively and significantly. After initiation of1α--(OH)-vitamin D₂ dosing, mean serum PTH decreases significantly toless than 50% of pretreatment levels. Due to this drop in serum PTH,some patients need to reduce their dosage of 1α--OH-vitamin D₂ to 4 μgthree times per week (or to even lower levels) to prevent excessivesuppression of serum PTH. In such patients, exhibiting excessivesuppression of serum PTH, transient mild hypercalcemia is observed,which is corrected by appropriate reductions in 1α--OH-vitamin D₂dosages.

At the end of the first 12-week treatment period, mean serum PTH is inthe desired range of 130 to 240 pg/mL and serum levels of calcium andphosphorus are normal or near normal for end stage renal diseasepatients. At the end of the second 12-week treatment period (duringwhich time 1α--OH-vitamin D₂ treatment is suspended and replaced byplacebo therapy), mean serum PTH values markedly increase, reachingpretreatment levels. This study demonstrates that: (1) 1α--OH-vitamin D₂is effective in reducing serum PTH levels, and (2) 1α--OH-vitamin D₂ issafer than currently used therapies, despite its higher dosages andconcurrent use of high levels of oral calcium phosphate binder.

The foregoing examples demonstrate that 1α--OH-vitamin D₂ is effectivein preventing or restoring the loss of bone mass or bone mineral contentwhile being substantially less toxic than 1α,25--(OH)₂ -vitamin D₃ and1α--OH-vitamin D₃. It is to be understood that although the foregoingexamples detail the use of 1α--OH-vitamin D₂, other compounds within thescope of the claims may be readily utilized in the treatment of thisinvention with essentially equivalent results. For example,1α,24(S)--(OH)₂ -vitamin D₂ shows activity equivalent to 1α,24(R)--(OH)₂-vitamin D₃ and is also significantly less toxic than its vitamin D₃counterpart. Also included within the scope of the claims would beadministration of effective dosages of the analog of formula (I) inconjunction with administration of other hormones or other agents whichhave been shown to stimulate bone formulation in subjects experiencingor tending toward loss of bone mass or bone mineral content.

Such hormones or other agents may include conjugated estrogens or theirequivalents, calcitonin, biphosphonates, calcium supplements, cobalamin,pertussis toxin and boron. Possible dose ranges for theseco-administered agents are provided in Table

                  TABLE 1    ______________________________________    Possible Oral Dose Ranges for Various Agents Co-Administered With    1α-Hydroxyvitamin D.sub.2               Dose Ranges    Agent        Broad     Preferred Most Preferred    ______________________________________    Conjugated Estrogens                 0.3-5.0   0.4-2.4   0.6-1.2    or Equivalent (mg/day)    Sodium Fluoride                  5-150    30-75     40-60    (mg/day)    Calcitonin (IU/day)                  5-800     25-500    50-200    Biphosphonates                  50-2000   100-1500  250-1000    Calcium Supplements                  250-2500  500-1500  750-1000    (mg/day)    Cobalamin (μg/day)                  5-200     20-100   30-50    Pertussis Toxin (mg/day)                   0.1-2000                            10-1500   100-1000    Boron (mg/day)                  0.10-3000                            1-250     2-100    ______________________________________

Although the above examples detail dosage by mouth, it is to beunderstood that the compounds can also be administered in alternativefashions, including intranasally, transdermally, intrarectally,intravaginally, subcutaneously, intravenously, and intramuscularly.

In summary, the present invention provides therapeutic methods forlowering blood levels of parathyroid hormone which are secondary to endstage renal disease. The method in accordance with the present inventionhas significantly less resultant hypercalcemia and hyperphosphatemia.

While the present invention has now been described and exemplified withsome specificity, those skilled in the art will appreciate the variousmodifications, including variations, additions, and omissions, that maybe made in what has been described. Accordingly, it is intended thatthese modifications also be encompassed by the present invention andthat the scope of the present invention be limited solely by thebroadest interpretation that lawfully can be accorded the appendedclaims.

We claim:
 1. A method for lowering or maintaining lowered serumparathyroid hormone in human patients suffering fromhyperparathyroidism, comprising: administering to said patients aneffective amount of a vitamin D analog to lower and maintain loweredserum parathyroid hormone levels, said analog comprising formula (I):##STR2## wherein A¹ and A² are either hydrogen or a carbon-carbon doublebond between C--22 and C--23; and R¹ is hydrogen or hydroxyl providedthat when A¹ and A² are a double bond, R¹ is hydrogen.
 2. The methodaccording to claim 1, wherein said analog of formula (I) is1α--OH-vitamin D₂ ; 1α--OH-vitamin D₄ ; or 1α,24(R)--(OH)₂ -vitamin D₄.3. The method of claim 1 wherein said analog comprises a dosage of 1 toabout 100 μg/week.
 4. The method of claim 1 wherein said analog, insolution, in a liquid vehicle ingestible by and nontoxic to saidpatients, is administered orally in encapsulated form.
 5. The method ofclaim 1 wherein said analog is administered in combination with at leastone agent characterized by said agent's ability to reduce loss of bonemass, or bone mineral content in patients.
 6. The method of claim 5wherein said agent includes other vitamin D compounds, conjugatedestrogens, sodium fluorides, biphosphonates, cobalamin, pertussin toxinor boron.
 7. The method of claim 1, wherein said administration of saidanalog is parenteral.
 8. The method of claim 7 wherein saidadministration is by subcutaneous, intramuscular, or intravenousinjection, nasopharyngeal or mucosal absorption, or transdermalabsorption.
 9. The method of claim 1 wherein said administration of saidanalog is nonparenteral.
 10. A method for achieving an effect in apatient comprising administering to the patient an effective amount of avitamin D analog of formula (I): ##STR3## wherein A¹ and A² are eitherhydrogen or a carbon-carbon double bond between C--22 and C--23: and R¹is hydrogen or hydroxyl provided that when A¹ and A² are a double bond,R¹ is hydrogen, and wherein the effect is lowering or maintaininglowered serum parathyroid hormone levels, and thus decreasing loss ofbone mass or bone mineral content.
 11. The method of claim 2, whereinsaid analog is 1α--OH-vitamin D₂.
 12. The method of claim 1, whereinsaid analog is co-administered with a calcium phosphate binder.
 13. Amethod of treating a human to alleviate or prevent the pathologicaleffects of hyperparathyroidism, wherein the method comprisesadministering to the human in need thereof a vitamin D analog selectedfrom the group consisting of 1α--OH-vitamin D₂, 1α--OH-vitamin D₄ and1α,24(R)--(OH)₂ -vitamin D₄ wherein said analog is administered to thehuman in an amount sufficient to lower or maintain lowered serumparathyroid hormone levels in the human to thereby alleviate or preventthe effects.
 14. A method for lowering or maintaining lowered serumparathyroid hormone in human patients suffering from secondaryhyperparathyroidism, comprising: administering to said patients aneffective amount of a vitamin D analog to lower and maintain loweredserum parathyroid hormone levels, said analog comprising formula (I):##STR4## wherein A¹ and A² are either hydrogen or a carbon-carbon doublebond between C--22 and C--23; and R¹ is hydrogen or hydroxyl providedthat when A¹ and A² are a double bond, R¹ is hydrogen.